Cancer is a significant health problem throughout the world. Although advances have been made in the treatment of cancer, no universally successful method for prevention or treatment is currently available. Cancer therapy currently relies on a combination of early diagnosis and aggressive treatment, which may include radiotherapy, chemotherapy or hormone therapy. The high mortality rate for many cancers indicates that improvements are needed in cancer prevention and treatment.
A wide range of growth factors coordinate cell proliferation and differentiation. Malignant cells arise as a result of a stepwise progression of events that include the unregulated expression of growth factors or components of their signaling pathways. Tyrosine phosphorylation events initiated by receptor, cytoplasmic and nuclear kinases and regulated by phosphatases are central to these processes. Mutation, hyper-activation, translocation and overexpression of protein tyrosine kinases are all associated with tumorigenesis. In addition to increasing proliferative rates and immortalizing cells, overexpression of other oncogenes can lead to morphological transformation and cause anchorage independence, contributing to the promotion of migratory ability and possibly the induction of metastases. Additionally, the inactivation and misregulation of cell cycle checkpoints and tumor suppressors are involved in tumorigenesis.
Cancer chemotherapy ordinarily involves the administration of one or more cytotoxic or cytostatic drugs to a patient. The goal of chemotherapy is to remove a substantially clonal population (tumor) of transformed cells from the body of the individual, or to suppress or to attenuate growth of the tumor. Tumors can occur in solid or liquid form, the latter comprising a cell suspension in blood or other body fluid. A secondary goal of chemotherapy is stabilization (clinical management) of the afflicted individual's health status. Often the tumor may initially respond to chemotherapy but in many instances the initial chemotherapeutic treatment regimen becomes less effective or ceases to inhibit tumor growth. The selection pressure induced by chemotherapy promotes the development of phenotypic changes that allow tumor cells to resist the cytotoxic effects of a chemotherapeutic drug. Often, exposure to one drug induces resistance to that drug as well as other drugs to which the cells have not been exposed.
Cell cycle checkpoints are regulatory systems that control the order and timing of certain events in the cell cycle. These checkpoints are important for ensuring that cells divide properly. For example, DNA damage leads to activation of a cell cycle checkpoint regulatory system that arrests the cell cycle and activates genes involved in repair of DNA damage. This system prevents progression of the cell cycle until the DNA damage has been repaired.
Thus, there is a need to identify factors that are involved in the DNA damage checkpoint pathway as well agents that can modulate the pathway. Agents that can modulate a cell's response to DNA damage may be used to decrease resistance in cancer cells by inhibiting a tumor cell's ability to resist the cytotoxic effects of a chemotherapeutic drug. The present invention satisfies the needs as well as others.